Murphy, Adam B. Biological and Environmental Mediators of Vitamin D and Aggressive Prostate Cancer! Candidate: Dr. Adam Murphy is an academic urologist who completed residency two years ago.
Adam aims to deepen his basic science skills to be a well-rounded translational scientist. He is in his final year of a mentored Department of Defense Physician Research Training Award focused on the role of vitamin D and related genetic polymorphisms in prostate cancer heath disparities. Dr. Kittles is the primary mentor on his DOD grant prepared Adam to lead related protocols and community-based projects. The career development provided by the proposed protocol would deepen his knowledge of immunohistochemistry, specimen processing, laser capture micro-dissection, tissue banking, genotyping and gene expression analysis. The current translational project focuses on validating serum and prostatic vitamin D as an anti-cancer agent with therapeutic potential in human prostate cancer tumors. The training plan includes Genetic Epidemiology and Clinical Trials will spur him to be an independent translational researcher. Environment: Adam has dual appointments at Jesse Brown VA Medical Center and Northwestern University in the Department of Urology. Also, Adam now has visiting researcher status at University of Illinois at Chicago. Dr. Andre K. Balla and Adam met over a year ago and have planned this protocol jointly with consultation from Dr. Kittles. Dr. Murphy has developed appropriate collaborations across 3 Chicago area institutions with the right researchers and a study coordinator. Dr. Murphy also developed a weekly Prostate Cancer Education Clinic for all men with newly diagnosed prostate cancer at Jesse Brown VA to provide education, to streamline the pathway to treatment and to facilitate research recruitment within the Jesse Brown Urology clinics. Research: Dr. Murphy's research protocols have been focused on database analysis, basic genetic data analysis and community based participatory projects. In order to be translational, Dr. Murphy will deepen his basic science skill set by training and mentorship provided by this project. Abstract: Vitamin D has anti-cancer properties in vitro in normal prostate epithelial cells, in prostate cancer cell lines, and in animal models. Activated vitamin D, 1,25 dihydroxyvitamin D, is known to reduce proliferation and promote apoptosis in prostate cancer cell lines. In several epidemiologic studies, vitamin D deficiency is associated with increased risk of prostate cancer and in some studies, aggressive disease. However serum vitamin D levels may not accurately reflect the vitamin D levels in the prostate as the normal prostate has the hydroxylases to activate and metabolize vitamin D. Prostate cancer cell lines have been shown to commonly lose 1-alpha hydroxylase activity with tumor progression. Therefore we seek to 1) validate serum vitamin D as a proxy for intra-prostatic vitamin D levels using the expressed prostatic secretion from 260 prostatectomy specimen;2) estimate the effect of vitamin D on rates of proliferation and apoptosis in 240 prostate tumors by evaluating percentage of cancer cells undergoing proliferation and apoptosis as a function of vitamin D tertile using a Ki-67 and a direct TUNEL assay on formalin fixed paraffin embedded tissue;3) evaluate for changes in relative gene expression in the vitamin D metabolic pathway with tumor progression in fifty low grade tumors (Gleason <6) versus fifty high grade tumors (Gleason 8-10).

Public Health Relevance

PCa is the most common cancer in men and is 50% more common in African Americans, which are over- represented in the veteran population. African Americans are at high-risk for vitamin D deficiency, advanced PCa and mortality.[49, 69] Low serum Vitamin D has been inconsistently linked to aggressive disease and higher PCa incidence.[21,22] Low expression of the vitamin D receptor is linked to PCa aggressiveness and mortality.[23] Activated 1,25 dihydroxyvitamin D decreases prostate epithelial proliferation and increases apoptosis in cell culture.[4] In vivo dat is needed to validate serum vitamin D as a biomarker for prostatic vitamin D, as a first step to therapeutic use.[20] Moreover, clarifying the associations of vitamin D status with PCa proliferation and apoptosis will provide mechanistic insight. Discovering gene expression differences with tumor progression may provide new biomarkers and groundwork for vitamin D-based interventions. The findings may significantly reduce the PCa burden and healthcare costs for the Veterans Health Administration.